Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[CH:30]>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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:30]#[C:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[F:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: C#Cc1ccccc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3ccccc3F)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To 0.502 g (1.161 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 67 mg (0.060 mmole) tetrakis(triphenylphosphine)palladium(0), 22 mg (0.116 mmole) copper (I) iodide, 10 mL degassed toluene, 0.484 mL (3.48 mmole) degassed TEA, and 0.199 mL (1.74 mmole) 2-fluorophenylacetylene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 0.440 g (89%) of a crystalline solid: 1H NMR (CDCl3/400 MHz) 1.35 (t, 3H, J=6.8 Hz), 4.26-4.38 (m, 2H), 5.83 (q, 1H, J=6.8 Hz), 7.08-7.15 (m, 2H), 7.18 (d, 1H J=2.4 Hz), 7.31-7.37 (m, 1H), 7.45 (d, 1H, J=2.4 Hz), 7.49-7.53 (m, 1H), 7.63 (s, 1H); (ES+) 425 (M+1, 100).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].[Sb](Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 68 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a mixed solution consisting of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-glucose and 299 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 68° C. for 8 hours. During this reaction, the refluxing solvent was dried with 35 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, 1.71 g of the starting sugar was recovered by filtration, and the reaction solution was diluted with chloroform, washed with aqueous sodium bicarbonate and water, and subsequently dried over anhydrous magnesium sulfate. The solvents including cyclohexanone were distilled off under reduced pressure, and the residue was recrystallized from ligroin to give 12.6 g (66.4%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose, m.p. 133°-136° C.
Reaction SMILES: CO[CH:3]([CH3:11])[C:4](OC)(OC)OC.[F:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[C:26]3[N:25]=[C:24]([NH:27][NH2:28])[NH:23][C:22]=3[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:19]=2)=[CH:15][CH:14]=1>C(O)C>[F:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[C:26]3[N:25]=[C:24]([N:27]4[CH:11]=[CH:3][CH:4]=[N:28]4)[NH:23][C:22]=3[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:19]=2)=[CH:15][CH:14]=1
Reactant: COC(C)C(OC)(OC)OC
Reactant: NNc1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Solvent: CCO
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-n4cccn4)nc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.012 ml of tetramethoxypropane was added to an ethanol (0.3 ml) solution of 8.3 mg of (4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-1H-benzimidazol-2-yl)-hydrazine, and the reaction liquid was stirred overnight at 80° C. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([O:18][CH3:19])(=[O:17])/[CH:14]=[CH:15]/[CH3:16]>ClC(Cl)C>[CH3:19][O:18][C:13](=[O:17])[CH:14]=[CH:15][CH2:16][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(=O)Cl
Reactant: C/C=C/C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCCCC(=O)CC=CC(=O)OC
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 26.5 g (0.2 moles) of aluminum chloride in 50 cc of dichloroethane is added a solution of 13.5 g (0.1 moles) of hexanoyl chloride and 10.0 g (0.1 moles) of methyl crotonate. Over a period of 10 minutes the temperature rises from 25 to 60°C. The reaction mass is refluxed for 4 hours at a temperature of approximately 90°C. The resultant methyl-5-oxo-decenoate is formed only in a small amount (approximately 2-3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH3:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.[BH4-].[Na+].Cl>CCO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O.CO.C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][CH2:14][C:13]2[CH:16]=[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11][CH:12]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: COc1ccc(N)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(NCc2cnc(Nc3ccc(OC)nc3)c(-c3nc(C)nc4[nH]cnc34)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (187.1 mg, 0.4200 mmol) was suspended in EtOH (3.8 mL) and tetraisopropoxytitanium (Fluka, Buchs, Switzerland, 0.25 mL, 0.84 mmol) and 4-methoxyaniline (Aldrich, St. Louis, Mo., 81.9 mg, 0.665 mmol) were added. DCM (2 mL) was added about 15 minutes later, and the reaction was stirred under nitrogen at room temperature overnight. Then, sodium borohydride (36 mg, 0.95 mmol) was added along with DCM (3 mL), and stirring was continued at room temperature, resulting in precipitation. After stirring for 1 hour, the suspension was treated with MeOH (1.5 mL) and 5 N HCl (0.60 mL). Stirring was continued at room temperature overnight. Then, the reaction was treated with water (20 mL) and filtered, and the solid was washed with water. The solid and unfiltered material were combined, concentrated, and treated with MeOH, and filtered. The filtration was sluggish, so instead the suspension was concentrated, treated with TFA and DMSO, and filtered with DCM and MeOH. This filtration was also sluggish, so the suspension was filtered instead through a Celite® (diatomaceous earth) pad. The filtrate was concentrated, but could not be filtered for HPLC purification despite treatment with DMSO, TFA, MeOH, and DCM. So, this solution was concentrated, and the fine suspension was filtered through a Celite® (diatomaceous earth) pad. This filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give 5-((4-methoxyphenylamino)methyl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (149.4 mg, 76% yield). MS (ESI pos. ion) m/z 469 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.60 (s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=2.54 Hz, 1H), 8.27 (s, 1H), 8.14 (dd, J=9.10 Hz, 2.45 Hz, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 6.97 (s, 2H), 6.90-6.80 (m 3H), 4.38 (s, 2H), 3.85 (s, 3H), 3.67 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1-c1cccnc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 3-pyridineboronic acid, the expected compound is obtained. The latter was not isolated and is used directly in the following stage.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[N:4]2[C:22]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:24]=[C:3]12.[Br:31][C:32]1[CH:33]=[C:34]2[CH2:40][CH2:39][NH:38][C:35]2=[N:36][CH:37]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:31][C:32]1[CH:33]=[C:34]2[CH2:40][CH2:39][N:38]([C:12]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][C:7]=3[O:15][CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)[N:4]3[C:22]([CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:23][CH:24]=[C:3]3[C:2](=[O:1])[NH:11]4)=[O:14])[C:35]2=[N:36][CH:37]=1
Reactant: Brc1cnc2c(c1)CCN2
Reactant: O=C(O)c1cc2[nH]c(=O)c3cnc(C4CCOCC4)n3c2cc1OCC1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2[nH]c(=O)c3cnc(C4CCOCC4)n3c2cc1OCC1CCOC1)N1CCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a mixture of 150 mg of 4-oxo-8-(tetrahydrofuran-3-ylmethoxy)-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid and 3 mL of N,N-dimethyl formamide were sequentially added 122 mg of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 0.25 mL of N,N-diisopropylethylamine, and 220 mg of HATU, followed by stirring at room temperature for 72 hours. The mixture was poured into a cooled saturated aqueous sodium hydrogen carbonate solution, followed by stirring for 30 minutes and extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0-92/8) to obtain 81 mg of 7-[(5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)carbonyl]-8-(tetrahydrofuran-3-ylmethoxy)-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: C(OC(=O)NC1SC(I)=CC=1C(N)=O)C1C=CC=CC=1.C(OC(=O)[NH:30][C:31]1[S:32][C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:34][C:35]=1[C:36]([NH2:38])=[O:37])C1C=CC=CC=1>>[NH2:30][C:31]1[S:32][C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:34][C:35]=1[C:36]([NH2:38])=[O:37]
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1NC(=O)OCc1ccccc1
Agent: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1
Product: NC(=O)c1cc(-c2ccccc2F)sc1N

Procedure:
The title compound was prepared as described in Intermediate 1 Step 4 using benzyl[3-(aminocarbonyl)-5-(2-fluorophenyl)-2-thienyl]carbamate (1.39 g, 3.74 mmol) as the starting material.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[S:23]>C1COCC1.CO>[NH2:8][C:7]1[C:2]([NH:1][C:22]([NH:21][C:15]2[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[S:23])=[CH:3][C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc(N)c(N)cn1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(N)cn1

Procedure:
Prepared analogously to example 360f from methyl 4,5-diamino-picolinate and 1,3-dichloro-2-isothiocyanato-benzene in THF and methanol.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:66][CH:67]=[CH2:68].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH:46]([O:58][CH2:68][CH:67]=[CH2:66])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg) in 9 ml 33% methylene chloride in cyclohexane was added allyl trichloroacetimidate (138 mg neat) and the reaction mixture was allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (18 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:4)+1% methanol) gave the title compound (230 mg; trichloroacatamide present). 1H NMR consistent with the desired structure.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=2)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([NH:32][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:30][N:31]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: COc1cccc(-c2cc(N)[nH]n2)c1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2367 gms. 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) over the weekend.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Nc1cccc(F)c1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(F)c4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 3-Fluoro-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(3-fluoro-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (7 mg, 14%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 6.78 (m, 2 H) 6.93 (m, 4 H) 7.39 (m, 1 H) 7.55 (m, 1 H) 7.74 (m, 1 H) 7.85 (d, J=8.46 Hz, 1 H) 7.97 (dd, J=8.82, 2.21 Hz, 1 H) 8.13 (d, J=1.84 Hz, 1 H) 8.88 (s, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.42 (s, 1 H) 11.34 (s, 1 H); MS (ESI+) m/z 510 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26]Cl)[CH:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C-:32]#[N:33].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:32]#[N:33])[CH:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [C-]#N
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) in ethanol (0.8 mL) and water (0.4 mL) were added NaCN (22 mg, 0.45 mmol) and KI (cat) at room temperature. The reaction mixture was stirred for 30 min at 110° C. in the microwave before being purified by column chromatography on silica gel (5-15% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 77%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:37])[NH:10][C@@H:11]([CH2:31][C:32]2[N:33]=[CH:34][S:35][CH:36]=2)[C:12](=[O:30])[NH:13][CH2:14][C:15]2[N:16]=[N:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=3)[CH:19]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>>[O:30]=[C:12]([NH:13][CH2:14][C:15]1[N:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:29])[NH2:27])=[CH:22][CH:21]=2)[CH:19]=1)[C@@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:37])[CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(S(N)(=O)=O)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(-n2cc(CNC(=O)[C@H](Cc3cscn3)NC(=O)[C@H]3O[C@@H]3C(=O)O)nn2)cc1
Yield: 2.8 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 42 (30 mg, 0.55 mmol); LiOH (1.3 mg, 0.055 mmol); product goes into aqueous layer during work up. Aqueous layer washed with CH2Cl2 and lyophilized to give the desired product as a white solid (8 mg, 45.1%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.92 Hz); 8.79-8.76 (t, 1H); 8.70-8.68 (d, 1H, J=8.0 Hz); 8.66 (s, 1H); 8.12-8.01 (m, 4H); 7.55 (s, 2H); 7.36 (s, 1H); 4.70-4.65 (m, 1H); 4.41-4.40 (d, 2H, J=5.20 Hz); 3.61 (s, 1H); 3.44-3.10 (m, 3H). 13C NMR (DMSO-d6, 100 MHz): 372.25, 170.66, 169.06, 165.74, 154.10, 152.52, 138.29, 146.80, 144.19, 128.01, 121.75, 120.59, 116.29, 53.25, 52.98, 51.84, 49.01, 33.43. HRMS-ESI: m/z [M+H+] calculated for C19H19N7O7S2: 522.0865, observed: m/z 522.0858 (M+H+); HPLC method 2: Rt=14.8 min; purity=95.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Reactant: Cc1cncc(Br)c1
Product: Cc1cncc(-c2cc(C)nc(C(=O)Nc3ccnc(Cl)c3)c2)c1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 3-Bromo-5-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=339.1, 341.1 (M+H)+.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH:30]=[CH2:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:52]1[CH:56]=[CH:55][S:54][CH:53]=1.[OH-].[Na+].Cl>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][CH2:31][C:52]1[CH:56]=[CH:55][S:54][CH:53]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Ic1ccsc1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: Cl
Product: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccsc3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Combine 9-borabicyclo[3.3.1]nonane (54.7 mL, 27.4 mmol, 0.5 M in THF) and (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and stir at ambient temperature. After 24 h, add triphenylphosphine (574 mg, 2.2 mmol), tetrakis(triphenylphosphine) palladium(0) (316 mg, 0.27 mmol) and 3-iodothiophene (1.93 g, 9.2 mmol). Add 3M NaOH (5.6 mL, 16.8 mmol) slowly, gas evolution occurs. Heat at reflux. After 48 h, cool to ambient temperature, add 5N HCl (12 mL), and stir 1 h. Extract with ethyl acetate and wash the extracts with 1N NaOH, water, brine, dry over sodium sulfate, filter and concentrate. Purify by silica gel chromatography using ethyl acetate/hexanes (10%) as the eluent to give 2.38 g of the title compound as an adduct of 9-BBN: mass spectrum (ion spray): m/z=377 (M+1).