Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CCCCCC>[CH3:32][C:31]([NH:35][Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)CCC3
Reaction time: 24 h
Yield: 91.3 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl)silane (5.3483 g, 0.01578 moles) was stirred in hexane (100 mL) as NEt3 (2.2579 g, 0.02231 moles) and t-butylamine (1.9898 g, 0.02721 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.4118 g, 91.3 percent).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 67 %

Procedure:
A mixture of 6-hydroxy-2,3-dihydroinden-1-one (8.1) (available from Aldrich) (5.0 g, 34 mmol), 1-(bromomethyl)benzene (available from Aldrich) (4.4 mL, 37 mmol) and cesium carbonate (25 g, 78 mmol) in DMF (40 mL) was stirred at room temperature for 23 hours. The resulting mixture was diluted with EtOAc (400 mL), washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give product 8.2 in 67% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: COCCC(=O)Cl
Product: COCCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 3-methoxypropanoyl chloride (18 mg, 150 μmol). Yield 17 mg (74%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@:7]1([CH2:40][CH:41]=[O:42])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C@@H:27]([CH2:37][CH3:38])[CH2:28][N:29]([CH3:36])[S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:32])=[O:31])[C:8]1=[O:39])(=[O:4])=[O:3].OOS([O-])=O.[K+].[CH3:49][OH:50]>C(Cl)Cl.O>[Cl:19][C:15]1[CH:14]=[C:13]([C@@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C@@H:27]([CH2:37][CH3:38])[CH2:28][N:29]([CH3:36])[S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[C:8](=[O:39])[C@:7]([CH2:40][C:41]([O:50][CH3:49])=[O:42])([CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CC=O)(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](COS(C)(=O)=O)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of ((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)methyl methanesulfonate (Example 414, Step F, 1.0 g, 1.516 mmol) in MeOH was treated with Oxone (0.932 g, 1.516 mmol) over a weekend. The reaction mixture was diluted with DCM and water. The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[O:34]=[C:35]([CH3:55])[CH2:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][CH2:36][C:35](=[O:34])[CH3:55])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCC(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(4-oxopentyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][CH2:6][C:5]([NH2:10])([CH2:8][CH3:9])[CH2:4][O:3]1.[C:12](O)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:11][C:2]1([CH3:1])[O:3][CH2:4][C:5]([NH:10][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:8][CH3:9])[CH2:6][O:7]1
Reactant: CCC1(N)COC(C)(C)OC1
Reactant: CCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NC1(CC)COC(C)(C)OC1

Procedure:
2,2-Dimethyl-5-amino-5-ethyl-1,3-dioxane is acylated wih dodecanoic acid in methylene chloride in the presence of DCC and 1-hydroxybenzo-triazole. Filtration and concentration gives the product.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:30][O:31][CH2:32][CH2:33][O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), 2-bromoethyl methyl ether (0.070 mL, 0.75 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column-chromatography eluting with hexane/AcOEt (1/2) to give the title compound (89.9 mg, 79% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.45 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 7.02 (1H, dd, J=1.9, 7.9 Hz), 7.20 (1H, s), 7.34-7.45 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 8.29 (1H, s). LC-MS (ESI) m/z 457 [M+H]+. Anal. Calcd for C23H19F3N4O3.0.25H2O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.87; H, 4.09; N, 12.15.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[Br:17]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:17][C:10]1[CH:9]=[CH:8][C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOc1ccccc1OCCOC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)cc1OCCOC
Yield: 99.6 %

Procedure:
1,2-Bis(2-methoxyethoxy)benzene (8.1 g, 31.9 mmol) and N-bromosuccinimide (6.2 g, 35 mmol) were stirred in 50 mL DMF at room temperature overnight. The reaction was diluted with 200 mL EtOAc and washed with 1N NaOH and water. The organic layer was dried over magnesium sulfate and concentrated to give 9.7 g (92%) of 4-bromo-1,2-bis(2-methoxyethoxy)benzene.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:17]1([NH:23][C:24]([O:1][CH2:2][C:3]2[CH:15]=[C:14]3[N:5]([C:6](=[O:16])[NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=43)[N:4]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.0 g (0.0093 mole) of 2-(hydroxymethyl)pyrazolo[1,5-c]-quinazolin-5(6H)-one prepared as described in Example 6B and 1.55 ml (≅1.7 g or 0.014 mole) of 98% phenylisocyanate are refluxed in 20 ml of dry pyridine under N2 for 1 hour. The crude product is poured onto 200 ml of ice-water layered with ethyl acetate (50 ml) and stirred for 30 minutes. The precipitates that form are filtered off, air-dried and taken up in dioxane (150 ml). The solution is filtered while hot and the clear filtrate concentrated down to a volume of 100 ml and cooled. The precipitates are filtered off and dried in vacuo at 85°. Yield 2.45 g, 78.8% crude yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1ccc(Br)cc1Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(Cl)c2)C1
Yield: 41.1 %

Procedure:
Preparation according to Preparation 1. 1-Bromo-3-chloro-4-fluorobenzene (5 g, 23.9 mmol) in dry tetrahydrofuran (100 ml), magnesium turnings (0.57 g, 23.9 mmol) and one crystal of iodine. 1-N-boc-3-pyrrolidone (4.41 g, 23.9 mmol) in dry tetrahydrofuran (50 ml). The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (3.1 g, 41%). MS m/z (rel. intensity, 70 eV) 214 (16), 157 (21), 143 (19), 129 (11), 57 (bp).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[N:51]=[CH:52][C:53]([C:56]2[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=2)=[N:54][CH:55]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[N:54][C:53]([C:56]3[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=3)=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: N#Cc1ccc(-c2cnc(N)cn2)s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccc(C#N)s3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of triphenylphosphine (50.0 mg, 0.191 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with N-bromosuccinimide (35.0 mg, 0.197 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 51.0 mg, 0.154 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-(5-amino-pyrazin-2-yl)-thiophene-2-carbonitrile (47.0 mg, 0.232 mmol) followed by pyridine (30.0 uL, 0.371 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH, 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(5-cyano-thiophen-2-yl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (44.4 mg, 55.9%) as a yellow foam: mp 101–107° C. (foam to gel); (ES)+-HRMS m/e calcd for C24H23ClN4O3S2 (M+H)+515.0973, found 515.0974.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)=[CH:3][N:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Brc1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: OCc1ccc(-c2ccnnc2)cc1
Yield: 63.7 %

Procedure:
To a solution of 4-bromopyridazine (131 mg, 0.824 mmol) in 1,2-dimethoxyethane (16.4 ml) were added 4-hydroxymethylphenylboronic acid (189 mg, 1.24 mmol), potassium carbonate (517 mg, 3.74 mmol) and water (8.2 ml), which was deaerated under reduced pressure, followed by argon substitution. Tetrakis(triphenylphosphine)palladium (73.5 mg, 0.0636 mmol) was then added, followed by heating to reflux for 5 hours under argon atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=0:1→1:4 (V/V), then methanol), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (97.7 mg) as a slightly brown solid. (Yield: 64%)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:38][CH3:39])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:22]>C(O)C.N1CCCCC1>[CH2:38]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:39]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (68 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2)CC1
Reaction time: 16 h
Yield: 47 %

Procedure:
A mixture of 3-aminopyridine (2.60 g, 27.60 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.50 g, 27.60 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.57 mL, 1.66 g, 27.60 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (7.02 g, 33.12 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→4:1) to yield 3.60 g (47%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, CDCl3): δ 1.28-1.41 (m, 2H), 1.47 (s, 9H), 2.04 (dd, J=12.8 Hz, J=2.6 Hz, 2H), 2.93 (t, J=12.3 Hz, 2H), 3.44 (br s, 1H), 3.58 (br s, 1H), 4.07 (d, J=10.7 Hz, 2H), 6.83-6.91 (m, 1H), 7.08 (dd, J=8.2 Hz, J=4.5 Hz, 1H), 7.96 (d, J=3.6 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H). MS (ESI): 278.5 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:43]=[C:44]([NH2:57])[C:45]4[C:49]([CH:50]=3)=[N:48][N:47](C3CCCCO3)[CH:46]=4)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:50]=[C:49]4[C:45]([CH:46]=[N:47][NH:48]4)=[C:44]([NH:57][C:6]([C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)=[O:8])[CH:43]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1c[nH]cn1
Reaction time: 0.08 h

Procedure:
1H-Imidazole-4-carboxylic acid (7 mg) in DMF (0.2 ml) was treated with N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (27 mg) in DMF (0.2 ml) and DIPEA (0.03 ml). The reaction mixture was shaken for five min prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg) in DMF (0.2 ml). The reaction mixture was shaken for five min and left to stand at 22° C. for 18 h. Solvent was removed in vacuo and the product re-dissolved in methanol (0.5 ml) prior to application on to an SCX SPE cartridge (1 g). The product was eluted after 1 h with 2M ammonia in methanol (2×3 ml), the fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) gave the title compound.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.Br.[CH2:19]([C:21]1[C:22]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([C:38]4[NH:39][C:40]5[CH2:45][CH2:44][NH:43][CH2:42][C:41]=5[N:46]=4)=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:23][C:24]([F:28])=[C:25]([OH:27])[CH:26]=1)[CH3:20]>>[CH2:19]([C:21]1[C:22]([C:29]2[CH:37]=[C:36]3[C:32]([C:33]([C:38]4[NH:39][C:40]5[CH2:45][CH2:44][N:43]([CH2:14][C:11]6[CH:12]=[N:13][C:8]([O:1][C:2]7[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=7)=[CH:9][CH:10]=6)[CH2:42][C:41]=5[N:46]=4)=[N:34][NH:35]3)=[CH:31][CH:30]=2)=[CH:23][C:24]([F:28])=[C:25]([OH:27])[CH:26]=1)[CH3:20]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(Oc5ccccc5)nc3)C4)n[nH]c2c1
Yield: 33.4 %

Procedure:
The title compound was prepared from 6-phenoxy-pyridine-3-carbaldehyde (39 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 24.7 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21](Cl)(=[O:23])[CH3:22].Cl[Sn](Cl)(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[C:21]([C:4]1[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[S:1][C:5]=1[NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])(=[O:23])[CH3:22]
Reactant: O=S(=O)(Nc1cc2ccccc2s1)c1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1c(NS(=O)(=O)c2ccc(Br)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To a suspension of compound 361-A (9.21 g, 25.0 mmol) in DCM (50 mL), cooled in an ice-bath, was added an ice-cold solution of acetyl chloride (2.30 mL, 32.3 mmol), followed by SnCl4 (27.9 mmol) in DCM (200 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was quenched with saturated NH4Cl solution (125 mL), filtered over a pad of celite, dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in refluxing EtOAc (75 mL), filtered hot and the filtrate allowed to cool. The solid was filtered and washed EtOAc (10 mL). Another batch of product was obtained by evaporation of the mother liquor, dissolving the residue in refluxing EtOAc (25 mL), filtering hot and allowing the filtrate to cool. The solid was filtered and washed with EtOAc (2 mL). The combined batches of solid were air-dried to afford 8.54 g of compound 361-B as a tan-orange powder. 1H-NMR (DMSO-d6) δ: 2.57 (s, 3H), 7.40-7.24 (m, 2H), 7.83-7.70 (m, 5H), 8.14 (d, 1H); MS: m/z 408.1 (M-H)−.